Selective Role of Intracellular Chloride in the Regulation of the Intrinsic but Not Extrinsic Pathway of Apoptosis in Jurkat T-cells

Heimlich, Gerd; Cidlowski, John A.

doi:10.1074/jbc.m507367200

Cited by 63 publications

(53 citation statements)

References 46 publications

(65 reference statements)

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“…(16). It is noted that inhibition of Cl Ϫ loss not only limits cell shrinkage but also prevents DNA degradation in human Jurkat cells following intrinsic activation of the apoptotic process (14). Inhibition of K ϩ loss will likewise limit the initial cell shrinkage but presumably also restrict decay of the membrane potential, which would normally favor Ca 2ϩ influx and activation of apoptotic enzymes (32,35,67).…”

Section: Resultsmentioning

confidence: 99%

Acquired cisplatin resistance in human ovarian A2780 cancer cells correlates with shift in taurine homeostasis and ability to volume regulate

Sørensen

Þorsteinsdóttir

Lambert

2014

American Journal of Physiology-Cell Physiology

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Sørensen BH, Thorsteinsdottir UA, Lambert IH. Acquired cisplatin resistance in human ovarian A2780 cancer cells correlates with shift in taurine homeostasis and ability to volume regulate. Am J Physiol Cell Physiol 307: C1071-C1080, 2014. First published September 24, 2014; doi:10.1152/ajpcell.00274.2014.-Cisplatin resistance is a major challenge in the treatment of cancer and develops through reduced drug accumulation and an increased ability to avoid drug-induced cell damage, cell shrinkage, and hence initiation of apoptosis. Uptake and release of the semiessential amino acid taurine contribute to cell volume homeostasis, and taurine has been reported to have antiapoptotic effects. Here we find that volume-sensitive taurine release in cisplatin-sensitive [wild-type (WT)] human ovarian cancer A2780 cells is reduced in the presence of the phospholipase A2 inhibitor bromenol lactone, the 5-lipoxygenase (5-LO) inhibitor ETH 615-139, and the cysteine leukotriene receptor 1 (CysLT1) antagonist zafirlukast and impaired by the anion channel blocker DIDS (4,4=-diisothiocyanatostilbene-2,2=-disulfonate). Comparing WT and cisplatin-resistant (RES) A2780 cells we also find that evasion of cisplatin-induced cell death in RES A2780 cells correlates with an increased accumulation of taurine, due to an increased taurine uptake and a concomitant impairment of the volume-sensitive taurine release pathway, as well an inability to reduce cell volume after osmotic cell swelling. Downregulation of volume-sensitive taurine release in RES A2780 cells correlates with reduced expression of the leucine-rich repeat-containing protein 8A (LRRC8A). Furthermore, acute (18 h) exposure to cisplatin (5-10 M) increases taurine release and LRRC8A expression in WT A2780 cells whereas cisplatin has no effect on LRRC8A expression in RES A2780 cells. It is suggested that shift in LRRC8A activity can be used as biomarker for apoptotic progress and acquirement of drug resistance. key word: platinum drugs; drug resistance; cell volume regulation; LRRC8A; TauT OVARIAN CANCER IS A LEADING cause of death among gynecological cancer patients, and the 5-yr survival rate has been estimated to 30% (64). The main reasons for the failure in treatment outcome are that 70% of the patients have already reached advanced stages of cancer progression at the time of diagnosis, i.e., the cancer has already spread within the pelvis and abdomen (68) and that most ovarian cancer cells rapidly develop resistance or multidrug resistance (MDR) against the chemotherapy.Cisplatin and chemotherapeutic resistance. Cisplatin was the first member of a class of platinum-based anticancer drugs, which also includes carboplatin and oxaliplatin (7,25), and today cisplatin is frequently used in chemotherapeutic treatment of ovarian cancer, lung cancer, and lymphomas (60). Cisplatin is administered to cancer patients intravenously as a sterile saline solution. Once circulating in the bloodstream, cisplatin is taken up by the cells and accumulated in the cell nucleus, where it causes DNA l...

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Section: Resultsmentioning

confidence: 99%

Acquired cisplatin resistance in human ovarian A2780 cancer cells correlates with shift in taurine homeostasis and ability to volume regulate

Sørensen

Þorsteinsdóttir

Lambert

2014

American Journal of Physiology-Cell Physiology

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“…FasL induces the activation of ORCC; however, net Cl Ϫ depletion does not occur during FasL-induced apoptosis, and thus, changes in intracellular Cl Ϫ distribution do not participate in the progression of cell death (62). We focused then on the role of K ϩ depletion in apoptotic cell death.…”

Section: Discussionmentioning

confidence: 99%

“…However, the exact mechanism by which the reduction in GSH i modulates the activation of the execution phase of apoptosis is still imprecise. A necessary role of K ϩ loss for the activation of execution caspases and apoptosome formation has also been demonstrated (5,60,61), whereas Cl Ϫ loss does not seem to play an important role in this phenomenon (62). Thus, we analyzed if the modulation of the execution phase of apoptosis by GSH transport was linked to the regulation of K ϩ loss.…”

Section: Gsh Regulates the Execution Phase Of Apoptosis By The Modulamentioning

confidence: 91%

Glutathione Depletion and Disruption of Intracellular Ionic Homeostasis Regulate Lymphoid Cell Apoptosis

Franco

DeHaven

Sifre

et al. 2008

Journal of Biological Chemistry

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Intracellular glutathione (GSH) depletion is an important hallmark of apoptosis. We have recently shown that GSH depletion by its extrusion regulates apoptosis independently of excessive reactive oxygen species accumulation. However, the mechanisms by which GSH depletion regulates apoptosis are still unclear. Because disruption of intracellular ionic homeostasis, associated with apoptotic volume decrease (AVD), is necessary for the progression of apoptotic cell death, we sought to evaluate the relationship between GSH transport and ionic homeostasis during Fas ligand (FasL)-induced apoptosis in Jurkat cells. GSH depletion in response to FasL was paralleled by distinct degrees of AVD identified by differences in cellular forward scatter and electronic impedance analysis. Inhibition of GSH efflux prevented AVD, K ؉ loss, and the activation of two distinct ionic conductances, mediated by Kv1.3 and outward rectifying Cl Apoptosis or programmed cell death is a ubiquitous energydependent, evolutionary conserved process. Under physiological conditions it is important not only in the constant turnover of cells in all tissues, but also during the normal development and senescence of the organism. Moreover, its deregulation has been observed to occur as either a cause or consequence of distinct pathologies (1, 2). A clear example is apoptosis mediated by Fas ligand (FasL) 2 receptor (Fas/CD95/Apo-1) activation, which is necessary for immune system homeostasis because of its role in the rapid clearance of immunoreactive T cells maintaining the immune balance and reducing the risk of autoimmune diseases (3). Apoptosis is a highly ordered process characterized by the progressive activation of precise pathways leading to specific biochemical and morphological alterations. Initial stages of apoptosis are characterized by activation of initiator caspases, changes in the cellular redox potential, intracellular ionic homeostasis, cell shrinkage or apoptotic volume decrease (AVD), loss of membrane lipid asymmetry, and chromatin condensation. Later stages associated with the execution phase of apoptosis are characterized by execution caspase and endonuclease activation, apoptotic body formation, and cell fragmentation (4, 5). Reduced glutathione (GSH) is the most abundant low molecular weight thiol in animal cells and is the major determinant in the redox potential of the cell. It is involved in many cellular processes, including antioxidant defense, drug detoxification, signaling, and proliferation (6 -10). Glutathione loss is an early hallmark in the progression of cell death in response to different apoptotic stimuli (11)(12)(13)(14)(15)(16)(17)(18)(19). Death receptor (including Fas)-induced GSH depletion has been clearly associated with the activation of a plasma membrane transport mechanism and not to its oxidation by reactive oxygen species (ROS) (20 -23). Several studies have shown a correlation between GSH efflux and the progression of apoptosis, and inhibition of GSH loss is able to rescue cells from cell death progress...

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“…Interestingly, it has also been proposed that Cl -channels may play a dual role depending on the specific type of cell death, such that Cl -channels have a protective effect if activated during necrosis, while having a cell-killing effect if activated during apoptosis [114]. Recently, Heimlich and Cidlowski [115] showed that the Cl -channel blocker SITS or medium with reduced chloride concentration diminished UV-C induced apoptosis in Jurkat T-cells, but was ineffective in preventing apoptosis induced through the death receptor pathway.…”

Section: Chloride As a Counter-ionmentioning

confidence: 99%

Cell shrinkage and monovalent cation fluxes: Role in apoptosis

Bortner

Cidlowski

2007

Archives of Biochemistry and Biophysics

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230

193

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The loss of cell volume or cell shrinkage has been a morphological hallmark of the programmed cell death process known as apoptosis. This isotonic loss of cell volume has recently been term apoptotic volume decrease or AVD to distinguish it from inherent volume regulatory responses that occurs in cells under anisotonic conditions. Recent studies examining the intracellular signaling pathways that result in this unique cellular characteristic have determined that a fundamental movement of ions, particularly monovalent ions, underlie the AVD process and plays an important role on controlling the cell death process. An efflux of intracellular potassium was shown to be a critical aspect of the AVD process, as preventing this ion loss could protect cells from apoptosis. However, potassium plays a complex role as a loss of intracellular potassium has also been shown to be beneficial to the health of the cell. Additionally, the mechanisms that a cell employs to achieve this loss of intracellular potassium vary depending on the cell type and stimulus used to induce apoptosis, suggesting multiple ways exist to accomplish the same goal of AVD. Additionally, sodium and chloride have been shown to play a vital role during cell death in both the signaling and control of AVD in various apoptotic model systems. This review examines the relationship between this morphological change and intracellular monovalent ions during apoptosis.

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Selective Role of Intracellular Chloride in the Regulation of the Intrinsic but Not Extrinsic Pathway of Apoptosis in Jurkat T-cells

Cited by 63 publications

References 46 publications

Acquired cisplatin resistance in human ovarian A2780 cancer cells correlates with shift in taurine homeostasis and ability to volume regulate

Acquired cisplatin resistance in human ovarian A2780 cancer cells correlates with shift in taurine homeostasis and ability to volume regulate

Glutathione Depletion and Disruption of Intracellular Ionic Homeostasis Regulate Lymphoid Cell Apoptosis

Cell shrinkage and monovalent cation fluxes: Role in apoptosis

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